We intend to suggest ways of designing penicillin and cephalosporin antibiotics which will be less susceptible to breakdown by Beta-lactamase defences of resistant bacteria, now that we have recently obtained the E. coli enzyme in a crystalline form suitable for X-ray analysis (J. Mol. Biol. in press, 1973). We are confident that a complete X-ray diffraction analysis of a penicillinase/penicillin complex will show in three dimensions where and to what extent various penicillins are bound to the active site on the penicillinase prior to and during catalytic breakdown to antibiotically inactive penicilloic acids. These stereochemical structural results will allow a precise determination of how organic chemists might change, by design rather than by trial-and-error, the penicillin molecule to prevent its recognization and destruction by the enzyme. The chemical modification must not, of course, alter the antibiotic's effectiveness against bacteria, probably due to its bring mistaken for one of the cell wall precursors during cell wall synthesis. We are therefore also looking for structural similarities between penicillin and N-acetylmuramic acid, D-alanyl-D-alanine, or L-alanyl-lambda-glutamic acid, again using X-ray methods of structure determination. This conformational analysis will establish whether penicillin is antibiotic during the polysaccharide polymerizing stage or at the transpeptidation cross-linking stage.